The intent of this proposal is to ascertain the effect of in vivo anti-4-1BB treatment on rhesus macaque cellular immune responses to SIV vaccination and/or infection. In so doing, we will explore new ways to stimulate SIV-specific cellular immunity and at the same time, determine the effect of this treatment on the course of disease in SIV-infected animals. Monoclonal antibodies to the 4-1BB receptor (CDw137), a member of the TNF receptor superfamily expressed on activated T cells and NK cells, preferentially stimulate CD8+ T cells in vitro and in vivo. Recent data suggests that ligation of the 4-1BB receptor on CD8+ T cells not only provides necessary co-stimulation and thus activation but may also prolong their survival. The latter effect is intriguing given the importance of CD8+ T cells in controlling viremia in both HIV and SIV infections. This proposal therefore addresses the areas of emphasis of the program announcement in that we are potentially identifying a co-stimulator that may optimize the CD8+ T cell response and ultimately be used as part of a vaccine against HIV. The specific aims are: 1) To test the in vitro effect of anti-4-1BB monoclonals on macaque lymphocytes in terms of activation, proliferation and cytokine secretion. 2) To determine the effect of anti-4-1BB monoclonals on CD8+ T cell responses induced by vaccination of Rhesus macaques with a DNA prime followed by a modified vaccinia Ankara (MVA) boost, both encoding SIVmac239 genes. 3) To administer anti-4-1BB during the course of an acute SIVmac239 infection and thus determine the effect of the treatment on viral loads, CD4 counts, anti-SIV CD8 activity and ultimately disease course.